Exploring the benefits of co-crystals in drug development

Here Dr. Thomas Kendall, application specialist at crystallisation and solid-state specialist Technobis Crystallization Systems, gives a perspective on the benefits of co-crystals and explains how they can be screened.

Key insights:

  • Co-crystallisation has become an attractive alternative to improve the physiochemical properties of drugs, like solubility and even taste, without affecting their pharmacology.
  • Co-crystals are used in the antipsychotic drug, Ablify - whereby scientists used a co-crystal with fumaric acid to ensure timely dissolution and improve the solubility and thermal stability of the drug.
  • Co-crystals can be formed with sweeteners and taste maskers as co-formers, which leads to an improvement in the taste of a drug.

Over the last decade, co-crystallisation has become an attractive alternative to improve the physiochemical properties of drugs without affecting their pharmacology. As a result of the pharmaceutical benefits co-crystals exhibit, industrial interest is on the rise.

When developing a drug product, solid formulations like tablets and capsules are often selected because of the benefits offered to patients. These benefits include high patient adherence, low variability between dosages and ease of taking the drug. However, solid formulations often have poor solubility, which can affect the absorption rate in the body.

There are several possible solid forms that can be investigated as part of the drug development process, each offering different physicochemical properties. A common strategy to increase the solubility of an ionisable drug molecule is salt formation. However, this approach is not suitable for non-ionisable materials, meaning scientists may look at alternative methods for solid state optimisation.

Co-crystals for solubility

An alternative strategy for improving solid state properties is co-crystallisation. The FDA defines co-crystals as “crystalline materials composed of two or more different molecules, typically API and co-formers, in the same crystal lattice”. Unlike salts, co-crystals do not rely on ionic interactions and can therefore be used for non-ionisable drugs.

An example of a drug that incorporates co-crystals is Abilify, otherwise known as Aripiprazole, an antipsychotic used in the treatment of schizophrenia. The drug exhibits poor aqueous solubility because of its twelve known anhydrous polymorphs. To improve the solubility and thermal stability of the drug, scientists used a co-crystal with fumaric acid. This ensured the drug would dissolve at the correct critical time.

Co-crystals can also be used if the solubility of a compound is too high and is absorbed too quickly in the body, modulating solubility for a sustained, slower release. One example of where this has been used is Ribavirin, an antiviral medication used to treat RSV infection and hepatitis C with barbituric acid.  

Improving taste

Taste has been shown to be an important factor in the acceptability and willingness of a patient to take oral drug products, especially in children, adolescents and the elderly. Co-crystals can be formed with sweeteners and taste maskers as co-formers, which leads to an improvement in the taste of a drug. This can be relatively straightforward, as many sweeteners and taste maskers are already FDA approved for application in food.

Theophylline, for example, is a drug used in therapy for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Scientists formed a co-crystal with saccharin, an artificial sweetener, which was found to improve the overall taste of the drug and mask bitterness.  

The co-crystal screening process

For scientists looking to use co-crystals to optimise their API during drug development, co-crystal screening is needed to identify candidates for characterisation. Co-crystal screening can be achieved using a number of techniques, including liquid assisted grinding or decreasing the temperature and driving supersaturation. Certain co-crystals will only be formed using certain techniques so it is important to use a wide range of screening methods. To avoid missing co-crystals, scientists can employ a systematic approach, which will also aid further development in the scale-up phase.

One popular tool for co-crystal screening is the Crystal16, which can be used to design an extensive co-crystal screening program by measuring the clear points of a series of co-formers and the API using 16 parallel reactors. By measuring the saturation temperatures of the mixtures, the possibility for co-crystallisation can be easily assessed.

Technobis Crystallization Systems develops several unique and proprietary technologies that aid in the research for crystallisation and solid-form.

Since 2005, platforms for accelerating crystallisation research have been successfully developed and installed in nearly every pharmaceutical research lab in the world. With more than 600 units in the field, a large community of scientists have been enabled to make a significant contribution to the accelerated development of new pharmaceuticals. In the last few years, new applications have been developed in agrochemical, fine chemical, military and (bio) fuel research, food and personal care creating new markets focused on understanding the importance of crystallisation research.

Technobis' workflow consists of:

  • The CrystalBreeder: the first crystalliser dedicated for both development and discovery, carrying out complete crystallisation screens with as little as 1mg of sample.
  • The Crystal16 parallel crystalliser: a multiple reactor station providing a screening solution for solubility determination, solid-state research, and process development: medium-throughput crystallisation studies at a 1ml scale.
  • With 8 independently controlled reactors and additional analytical capabilities, the Crystalline is a unique modular product line at a working volume of 5 ml for solid-state research, process development and formulation research.